Aurora-A转录激活乳腺癌细胞PD-L1导致抗肿瘤免疫抑制的机制研究

Tumor immune escape is an important cause of tumorigenesis. Aurora kinase A (Aurora-A，Aur-A) is a serine/threonine kinase which involved in the regulation of cell mitosis. Dysfunction of Aur-A promotes breast cancer formation and metastasis. However, its involvement in anti-tumor immune responses is not fully elucidated. Our previous work showed that there was a positive correlation between the expression of Aur-A and PD-L1 in breast cancer cell line. In addition, IL-2, IFN-r and PRF-1 expression in the immune cells was increased when blocking breast cancer cells Aur-A activity by Aur-A inhibitor AKI603. Therefore, we hypothesized that overexpression of Aur-A might suppress the anti-tumor immune response in the breast cancer. Based on the animal model (J Immunol 2013), we established a NOG mouse model with human immune reconstitution bearing human breast cancer and observed the effects of immune cells on breast cancer cells in vivo system. In this study, we intended to investigate the precise mechanism of PD-L1 induction by kinase activity or transactivating function of Aur-A. Secondly, to elucidate the immune suppressive function of Aur-A, we intended to analyze the number of tumor infiltrated effector/suppressor cells, the expression of activation receptor, cytokines and cytotoxicity of the immune cells. Finally, using the NOG mice breast cancer model, we intended to approve the enhancive effects of AKI603 on immune cells and compare the therapeutic effects of AKI603 alone or in combination with anti-PD-L1 antibody for treatment of Aur-A high expression breast cancer. Our study would reveal the immune suppressive mechanism of Aur-A and provide a new approach to the treatment of breast cancer.

细胞免疫逃逸是肿瘤发生的重要原因，Aurora-A（Aur-A）蛋白激酶在肿瘤发展中异常表达，而其异常是否参与调控肿瘤免疫逃逸尚未知。前期实验发现乳腺癌细胞的Aur-A诱导PD-L1表达。下调Aur-A活性可提高免疫细胞IL-2、IFN-γ等因子表达，提示Aur-A异常参与免疫逃逸。申请者利用前期的动物模型基础（J Immunol2013）建立了人源性荷乳腺癌小鼠模型，成功模拟人体内免疫细胞对乳腺癌细胞的作用。本课题拟从Aur-A的蛋白激酶与转录激活功能两方面探讨其调控PD-L1表达的分子机制。再研究Aur-A表达对肿瘤浸润的效应/抑制性免疫细胞数量、活化受体表达、细胞因子分泌及杀伤功能等影响，阐明Aur-A及其下游信号通路调控肿瘤免疫应答的机制。最后研究Aur-A小分子抑制剂单独或联合PD-1抗体对免疫反应的调节作用。本课题将明确Aur-A调控肿瘤免疫逃逸的机制，为乳腺癌治疗提供新途径。